title: Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics.
abstract: Relatively little is known about the viral factors contributing to the lethality of the 1918 pandemic, although its unparalleled virulence was likely due in part to the newly discovered PB1-F2 protein. This protein, while unnecessary for replication, increases apoptosis in monocytes, alters viral polymerase activity in vitro, enhances inflammation and increases secondary pneumonia in vivo. However, the effects the PB1-F2 protein have in vivo remain unclear. To address the mechanisms involved, we intranasally infected groups of mice with either influenza A virus PR8 or a genetically engineered virus that expresses the 1918 PB1-F2 protein on a PR8 background, PR8-PB1-F2(1918). Mice inoculated with PR8 had viral concentrations peaking at 72 hours, while those infected with PR8-PB1-F2(1918) reached peak concentrations earlier, 48 hours. Mice given PR8-PB1-F2(1918) also showed a faster decline in viral loads. We fit a mathematical model to these data to estimate parameter values. The model supports a higher viral production rate per cell and a higher infected cell death rate with the PR8-PB1-F2(1918) virus. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PB1-F2 on the possibility of a pandemic and on the importance of antiviral treatments.
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Adler
authors.forename: Julie L
authors.initials: JL
authors.lastname: McAuley
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Gutenkunst
authors.forename: Ruy M
authors.initials: RM
authors.lastname: Ribeiro
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity / Q000502:physiology*; D007700:Kinetics; D016014:Linear Models; D008168:Lung / Q000821:virology; D051379:Mice; D008954:Models, Biological; D009976:Orthomyxoviridae Infections / Q000821:virology*; D058873:Pandemics; D019562:Viral Load; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics; D014779:Virus Replication / Q000235:genetics* / Q000502:physiology
chemical_list: C442816:PB1-F2 protein, Influenza A virus; D014764:Viral Proteins